Thank you so much for coming to this workshop. I tried to make it as interactive as possible so that you won't get bored. I'm Dr. Hiroko Furo. I'm an assistant professor in addiction medicine at the University of Texas at San Antonio. So we are going to talk about how, oh, by the way, can you hear me okay? Okay. How to interpret urine test results and identify manipulation in buprenorphine treatment. I'm just curious, how many people ever have prescribed buprenorphine? How many people will check the urine test every day? Every day? Not every day, but you know, regularly. Regularly. Okay, so you guys are familiar. Okay, so that's good to know. All right. All right, so there is no disclosure. There's nothing to disclose. And the learning objective for this lecture or the workshop is to identify the features of opioid use disorder, understand how to monitor the treatment outcome, interpret the urine drug screening test results more accurately. So there's three parts. Each takes about 45 minutes or so, but I tried to make it as quick as possible at the same time interactive. So the first one is the features and treatment of opioid use disorder. Two, the research study that we just published. And three, we'll actually do some cases to practice. Okay, so let's start with some questions. There are eight questions. What are the three FDA-approved opioid use disorder medications, and how do they work? How are they different? Why is naloxone added to buprenorphine often in a certain formulation? What are the differences between brand-name buprenorphine naloxone versus genetic buprenorphine naloxone? What's the half-life of bup? And which P450 enzyme metabolizes buprenorphine primarily? Which substances are dangerous to combine with bup? What are the common side effects of buprenorphine? How should we take buprenorphine? Anyone can answer all the questions. Good. Could you do me a favor? Could you make a two- or three-up to four-person group and then discuss quickly these questions? There is only one person who can answer, but could you make a group, two- or three-people group, and then discuss it? It will take three minutes. All right. I'm sorry. I'm going to stop the discussion and then move on. The first part, we are going to talk about—you might want to stay, though, because we are going to do a lot of group discussion. This is the opioid prescription trend. As you can see, the prescription has been going down in the last one, two decades or so. However, the overdose death has been increasing because of the synthetic opioid and because of the heroin, fentanyl, carfentanil. They are so potent. A small amount can kill. Not only the heroin opioid itself, but sharing the needle can spread the infectious disease, so we have to pay attention to that. Opioid use disorder, substance use disorder, we always use the DSM-5. This is the first question. FDA-approved medications, methadone, buprenorphine, naltrexone. Buprenorphine is the full agonist—I mean the methadone full agonist, buprenorphine partial agonist, and naltrexone or naloxone is the antagonist. So there is the differences. Okay. And then buprenorphine formulation. There are so many different formulations—pills, films, and injections, and so forth. The enzyme, mainly P450-384, and the half-life is about one to two days. Why it's important, we're going to talk about that later. Okay. And then opioid receptors, we focus on mu receptor because it can cause euphoria and addiction, and also it can cause respiratory depression, which can cause death, overdose death. But I want to know that there are some different receptors as well. All right. So buprenorphine is pretty safe because of what is called the seeding effect. So even though if you take too much, there is the seeding effect, so it's unlikely to get respiratory depression and death unless you will take certain medication at the same time. For example, FDA recently, 2017, issued the strongest warning against combining opioid pain or cough medication with benzoyl, and also CNS depressant is on the black box warning. So we have to make sure our patient is not taking buprenorphine with benzodiazepine. Cough medication. Oh. Yeah. What cough is it? Dextromethorphan? Yes. Dextro? Yes. Some of the opioid medication. Yes. And even though the buprenorphine is pretty safe, by the way, I'm going to use buprenorphine and Suboxone interchangeably. Yes. Did you say dextromethorphan or opioid? Dextromethorphan is also, I think, included in the cough medication warning. And that was actually for full agonists, though. That wasn't buprenorphine. So they came out with a, first they came out with this in 2016 and said don't ever do it, but then they came out in 2017 and said be very careful because they didn't want people not starting buprenorphine if someone was on benzodiazepine. You know, they just want you to be very careful and know that that's okay. For the recording, could we go ahead and make the requests on the mics, please? Oh, okay. Okay. Yes. Thank you. Thank you. This is the FDA adverse event reporting system, and from the year 2000, 2,626 people died by suspected Suboxone overdose. So even though Suboxone itself is considered safe, but we have to be careful. How to take Suboxone or buprenorphine, there is the vessels under the tongue, and they put the films or pills under the tongue and get it dissolved completely. And I usually encourage my patient to practice 15-minute rule, no eating, drinking, or smoking 15 minutes before and 15 minutes after, and take up to 15 minutes and take the medication, get it dissolved completely. And these are the side effects, but I hear a lot of my patients saying constipation, leg swelling, and also itchiness, and some kind of sexual side effects as well. All right, and also FDA issued a warning, I think it was 2022, okay, about the dental problem with buprenorphine medication. So we have to encourage the patient to have the dental hygiene. Okay, so how to monitor the treatment outcome. So we usually use the PMP, prescription drug monitoring program, and urine drug testing. But we are not police or a judge, we are clinicians. So the main purpose of using these tools is to help the patient, not to judge the patient. Okay, so I hope you can answer all the questions by now. Any questions? Okay, so let's move on to the part two, which is based on our study. It was published last year, around this time, December 2021. Buprenorphine dosage and urine, quantitative buprenorphine, no buprenorphine, and creatine was in the office-based opioid treatment program. The reason why I started this research is that because we face a lot of challenges in interpreting the urine samples. So let's look at this. This patient, buprenorphine, we used the Quest lab, so this is like one of the examples. Buprenorphine is 6, no buprenorphine is 26, and creatine is 68. And patient comes up to me and said, Dr. Furoh, I still have cravings. Would you increase my dosage from 12 to 16 milligrams? How many people will increase? How many people decrease? How many people stay there, stay the same? Okay, all right, all right. So that's what we're going to talk about. So, you know, we face this kind of situation all the time. So how should we handle it? That's the whole purpose of doing the research. So the retrospective chart review and buprenorphine intakes were observed at four halfway houses. And 41 patients with 240 urine samples were used. And the buprenorphine, no buprenorphine, creatine levels were checked in the urine samples. So let's start with the buprenorphine metabolism. Buprenorphine is metabolized to buprenorphine gluconide and then no buprenorphine. And these are free no buprenorphine and free buprenorphine. And then buprenorphine gluconide. And no buprenorphine is further metabolized to no buprenorphine gluconide. So when we look at the lab result, when we look at the buprenorphine, this means that these two are included. When we look at the no buprenorphine, these two are included. So look at this. So buprenorphine, this means free buprenorphine and buprenorphine gluconide. And no buprenorphine, this means free no buprenorphine and no buprenorphine gluconide are involved. Okay, so let's talk about previous studies about buprenorphine, no buprenorphine, and creatine levels. Oops. One study said that no buprenorphine level could be used to guide dosing of buprenorphine because it's a metabolite. And the compliant patients have more no buprenorphine than buprenorphine level, while intermittent buprenorphine intake resulting low no buprenorphine level. And we have to check creatine because creatine, urine creatine, allows for standardization of levels despite fluctuation in urine concentration. So, you know, urine can be diluted or concentrated. So not only looking at the no buprenorphine level or buprenorphine level is not enough. You have to check creatine level as well. Okay, so let's look at this urine test. Buprenorphine is 110, no buprenorphine 229, creatine is 41. How many people think that this is appropriate? How many people think this is inappropriate? Inappropriate? Appropriate? Appropriate. One more time. Appropriate. How many people appropriate? How many people inappropriate? How many people no clue? So we'll learn about that. Okay. All right. I like this study. This study used 18 volunteers and give a small, very small amount of buprenorphine film, 0.4 film, a milligram film given to the 18 volunteers. And they checked their urine and they get like 170 urine sample from the 18 volunteers. And try to look at the bup and no bup ratio. And then four hours, eight hours, and so forth. And they found that around seven hours after they take the buprenorphine, the no buprenorphine get higher. So at the beginning, buprenorphine is high, no buprenorphine low, because, you know, no buprenorphine is metabolites. But after seven hours, they switch and no buprenorphine get lower, buprenorphine is higher. That makes sense, right? Because it's a metabolites. So no buprenorphine and buprenorphine rate may be used to estimate the time of intake. There is lots of, you know, variation, but this is, you know, kind of one study that we can look at. Okay, so let's look at this patient, this case. Buprenorphine is 285, no buprenorphine 195, creatinine is 88.9. Oops. What do you think? Why this buprenorphine is higher than no buprenorphine? I'm sorry? Yes, they just take it. Probably within seven hours. Yes, so that's why, you know, probably this patient had buprenorphine is higher than no buprenorphine. Right? Everyone agree? Okay, all right. So let's move on to next. Okay, so next one. Look at this. All right. So, oops, sorry about that. Oh, okay. Let me, you can see them. Okay, so buprenorphine here is 2,000, above 2,000. That's a lot. They can't measure. No buprenorphine is 15. Creatinine is 40. What's going on? Yes? They dumped buprenorphine in the urine. Yes, exactly. So what they did is they dipped the buprenorphine. So there are some free buprenorphine and free no buprenorphine. So that's why buprenorphine is very high. So this is what is called adulteration, dipping, spiking, tampering. You know, this is the, so we can check by looking at the urine how they are, the adulteration. There is so many research done about adulteration. For example, one study said that no buprenorphine, buprenorphine ratio more than 50 to 1 indicate tampering or adulteration. Buprenorphine more than 700 could indicate adulteration. All suspected samples of spiking, spiking the same as adulteration, contain buprenorphine level greater than 2,000, with the mean no buprenorphine about 12, indicate adulteration. So these studies saying that buprenorphine really high, like 50 to 1, and no buprenorphine 1, could be the indication of adulteration. So we have to pay attention to that. So let's look at the next case. This case, buprenorphine level is 2,000, more than 2,000. That means high. No buprenorphine is 15, and creatinine is 40, 40.8 by 40. So, I'm sorry, this is the case of adulteration, right? Everyone understand? Okay, good, good. That's a good question. I'm doing some research on that. I'm going to publish the paper. When we put the buprenorphine to the urine, even water, there is a small amount coming in. So it's a dissolvent, as opposed to metabolite. That's a great question. But, yeah, I'm working on the research. Okay, all right. So, so far everyone agreed, right? Okay, all right. Let's move on to the next one. Buprenorphine, this one, buprenorphine is 309. No buprenorphine is negative, less than cut point, which is 2. Creatinine is 0.1. What's going on? Anyone? Huh? Dilution, yes, yes. Okay, so look at this one. Previous studies on dilution, dilution manipulation could be detected measuring the creatinine level. So some people, you know, there is urine and put the water to make it so diluted so that all the substance cannot be detected, right? And usually, oops, I'm sorry. Usually the men and women, but usually 20 is the cut off normal range up to about 300, depends on the gender. But so if it's less than 20, we have to pay attention. Is that the dilution manipulation? So let's look at this one. So one more time, what's going on? Buprenorphine is 309, no buprenorphine negative, creatinine is 0.1. Dilution and? Yes, so this is the combination, can you tell? Because this creatinine level is very low, so that's dilution, right? But, you know, the buprenorphine and the no buprenorphine ratio is very high. So that means that there is the two manipulation going on. Put the water and then dipped so we can tell that, you know, patient did something on their urine. Is that okay so far? All right, all right. So let's move on to, okay. So, but, you know, when we look at the urine and then creatinine level is less than 20, we cannot just jump into the conclusion, oh, this patient had adulteration. We have to think about other possibility. We don't want to judge, you know, jump to the conclusion and judge. Some of the reason, of course, you know, manipulation, but sometimes during the summertime, they are so hot outside, they are dehydrated. So they drink water before taking the urine test, urine correction. Excessive hydration to overcome urine retention from buprenorphine use. So it's a rare but possible side effect of buprenorphine is that retention, urine retention. So they can't pee. So they try to drink lots of water before the urine correction so that dilution of urine can happen. And then age and gender can lower the urine concentration, kidney disease, muscle wasting. Also, if the patient has diabetes, specific diabetes, insipidus diabetes, they have to, you know, they get so thirsty, they drink lots of water. And also certain medication, diluted medication can cause the urine very thin. So, you know, we can't just jump into the conclusion like at 20, oh, less than 20, oh, this patient is putting the water, but we have to look at the whole picture. Okay, so going back to research, this is the research. We use the halfway house resident, and the research time is one year, 2018 to 2019. The reason why we use the resident data is that in the halfway house setting, their medication is controlled by the staff, and they give the medication every day, every time they take the medication. And they have to take the medication in front of the staff. So it's very hard to manipulate the intake. And also most of the, not all of them, but if it's not, most of them, urine correction is observed. So it's very hard to manipulate their urine test. So that's why we choose this population. We use the New York PMP to make sure their buprenorphine naloxone dosage. This is just an example of the PMP in New York. And inclusion criteria, oh, by the way, how many people checked the PMP? Okay, good, so you are familiar, okay. All right, so inclusion criteria for this study is the patient who live in the halfway house during the one-year period, and then they have the opioid use disorder diagnosis, who was on buprenorphine product, and whose buprenorphine information was confirmed on the PMP. And we have to have the buprenorphine, no buprenorphine, and creatine level available in the Quest lab. And also patients should be at least seven days in the halfway house to make sure their urine is reflected of their monitored intake. And then regarding the exclusion criteria of the urine, there is one sample which has the THC, so it was removed from the data. And another exclusion criteria was the creatine less than 20, but all of the urine tests, urine had the creatine more than 20. So we only excluded one urine test, urine. And some buprenorphine and no buprenorphine levels are listed as more than 2,000. And in that case, we used 2,000 to do the calculation. Okay, so this is the patient selection flowchart. We were able to get 281 halfway house residents, and then 166 out of 281 is the opioid use disorder diagnosed. And then out of 166, 89 patients have the PMP confirmed with the buprenorphine treatment. And then Quest lab available out of 89 is 41, and there are 240 urine tests. Okay, all right, this is the demographic information of 41 patients. And then we put all the information on the Excel and did the analysis. Okay, so let's go to the result. So this is the patient, let's start with the dosage. Out of 41, the patient take four milligram to 20 milligram of Suboxone or buprenorphine. And, oh, by the way, all the patient has buprenorphine naloxone genetic films. And the patient range from four milligram to 20 milligram, and the highest is eight milligram, 17 patient, and 12 milligram, 10 patient, and 16 milligram, 6 patient. How many people ever work in the detox or inpatient? Okay, from my experience, I rarely give 20 or 24 in the setting, because when we start giving 24, they complain for drowsiness and so forth. So from my experience, this agrees. And also there are some research regarding the dosage. This is the study PET scan of the brain and the opioid receptor availability. When the patient get no buprenorphine, there's lots of red, yellow, and green spot indicating there are empty opioid receptors. If they take two, it's getting smaller, 16 and 32. 16 and 32, there is not much difference, right? And also opioid receptor, so after 16, there is not much difference, but lots of side effect. So I personally give up to 16, except certain cases. And there is another study saying that 16 milligram is typical. 16 to 24, patient difference variation. Up to 24, we have to monitor. Okay, but there are some exceptions, right? For example, patient who has a high metabolism. Pregnant patient who have like two in one body and post-op. So recently there are buprenorphine, small amount of buprenorphine continued and add morphine or opioid to control the surgery pain. So they might need certain more suboxone of buprenorphine after this kind of operation. Some of the pain patients prefer three times a day. But whenever they ask more than 16, I usually check their urine. And they said, oh, there is 2,000, 2,000, 2,000. This is a patient who has a high metabolism. Then probably I will give some medication. But important thing is that we have to take all the pictures of all the information of the patient. Medication, medical issues with urine test and so forth. Okay, all right. So then let's move on to the urine samples. There is 240 urine samples. And the highest, 83 samples came from the patient who are on 12 milligram a day. 66 sample came from 8 milligram a day. And then 35 sample came from 16 milligram a day patients. So we decided to focus on three groups. Okay, so and then this is the summary of the urine analysis. So buprenorphine, no buprenorphine, creatinine, buprenorphine to no buprenorphine, buprenorphine to creatinine, and no buprenorphine to creatinine ratio. Those are listed in each group, 8 milligram a day group, 12 milligram a day group, 16 milligram a day group. Yes, you have a question. Can you go back to the pregnant patients? Because my understanding is for methadone, you do have a higher dosing with higher metabolism. But for buprenorphine, does that result change that much? I usually check the urine and then no buprenorphine level and then creatinine level. If it's high, I don't mind. But it really depends on each person, each situation. If the patient is complaining for cravings, I would give the medication. Yeah, the only person I ever end up for pregnant patients is for the twins, because pregnant twins have low metabolism. Yeah. So most of the time I do that, but I'm just curious. Yeah, sometimes, I usually, when I see the pregnant patient, their urine no buprenorphine is very high. So in that case, I will increase the dosage. Okay, so as you can see here, creatinine level, the lowest creatinine level is 25 here. So every urine test is creatinine level more than 25. Buprenorphine and no buprenorphine ratio, the highest is 5, about 6. So probably there is no dipping going on. And then also we check the no buprenorphine and creatinine level. And these are the three. And this is like a chart, a graph of the three groups. And we check the means, we compare the mean using ANOVA. And we can see that there is the statistical difference among the three groups. P-value is less than 0.05. But post hoc analysis shows that there is no statistical difference between the 12 mg and 60 mg group patient. So it could be probably due to the seeding effect. But also we did the log transform data because the data is, the power is not that strong. But when we use the log transform data, the results are very similar. So, and then some people ask, so what's the appropriate dosage? We are working on the second research study using the two years more data. And we found that when we look at the means, there is not much difference. But when we look at the median of each group, there is a pretty, fairly good association. So if they are taking 60 mg, the median is 5.5. So if the ratio between no bup to creatinine ratio is 4 to 5, probably they are taking the medication as prescribed. If the patient is 8 mg, maybe around 4, then the patient might be taking, probably taking the medication as prescribed. If they are on 12, probably around 5. And those are the median, but there is a variation. So let's go back to the current study. So look at the, I want you to focus on this lowest. There is lots of outliers, but when we look at the lowest, 8 mg, 0.4. 12 mg group, 1.6. And then 60 mg, 1.4. So if the patient is, urine has this, probably they are taking the medication. But if it's not, maybe we have to monitor closely. So the reason why low no-buprenorphine level. There are some reasons. For example, inconsistent buprenorphine intake, low metabolism, liver diseases that they can't metabolize the buprenorphine, and age and gender, we have to take into consideration. And also for the 3A4 activities. And also certain medications inhibit the 3A4 enzyme activities. These are listed here. So we have to talk with the patient and see what's going on. Okay, so as a summary, this is what is called alarming features. If we see unexpected substance in the urine, maybe heroin or benzo alcohol, we have to pay attention. And if the creatinine level is less than 20, we have to pay attention. That doesn't mean that we have to discharge the patient or we have to judge that this patient's urine is not appropriate. But we have to pay attention. And also if the patient's buprenorphine, no-buprenorphine ratio is more than 50 to 1 for possible adulteration, buprenorphine dosage over 24, and no-buprenorphine creatinine ratio is below 0.5 in the patient who are on eight milligram a day, or 1.5 in patient who are treated with 12 milligram or more a day. Yes? I have a question. You mentioned like in seven hours that no buprenorphine dose increase and then it becomes more than, when you are doing these samples, what time of the day are you doing them? Like I have a lot of patients who takes twice a day. So if they took the dose in the morning and then you are testing, how would you interpret since like we don't know when the no buprenorphine level will come? How to interpret that? That's a great question. So there is lots of variation. The question is that there are lots of people who are taking a certain time. We are going to go on that with some cases, okay? All right, so these are learning features. So that doesn't mean that we have to discharge the patient immediately. What we have to do is we have to sit down and talk and then find out any other situation, reasons to think about. One of the thing we can do is the patient education. Sublingual buprenorphine intake can be tricky. I have one patient who doesn't like the film and I ask him why. And he said that when he swallowed the film, it's get really itchy. No, no, no, no. Film should be under the tongue, you know? Because patients are so used to the pills. So they take, they swallow. Also noncompliance. Okay, so you know, I reinforce the 15 minutes rule. Put it under the tongue, 15 minutes, no eating, drinking, smoking, 15 minutes before, 15 minutes after. By the way, do you know why we shouldn't smoke? Huh? Yes, exactly, vasoconstriction. So the vessel can be a bit hard for the vessels to absorb the suboxone. Yeah, good, good job. All right, so let's talk about noncompliance. Some patient who are traveling or so busy and they forgot to take buprenorphine film. I understand. In that case, you know, we have to encourage them to be compliant. And then also we have to worry about diversion. When I look at the last information, eight film, buprenorphine slash nonbuprenorphine, buprenorphine slash naloxone, like $10 to $25 a day. So if they take two films for one month, that's a good livelihood for some of the patient. So, and there is some, you know, reasons, motivation or incentive to divert. And some research, some people said that many albedo use disorder patients obtain diverted buprenorphine for reasons such as difficulty accessing legitimate treatment program. However, because of the COVID, there are lots of telemedicine going on. So they're getting easier and easier to get to the access to the legitimate treatment center. And also if they are still connecting to the leaders, you know, getting the buprenorphine to someone else, I find it very difficult to, you know, to stop the, it's easy to relapse because of the connection. And also those on diverted buprenorphine could be helped by providing them with the opportunity to engage in appropriate treatment program where their treatment will be structured for the optimal patient care. In the state of Texas, the possession of unprescribed controlled substance is a felony. And I don't want to help them to commit a felony like that. So, and I think if they go to the appropriate treatment program, they can, we can monitor them and then, you know, help them better. So, and for example, our program, if patient doesn't have any money, we have financial support. So I'm sure there are some kind of support we can look for. So anyway, so limitation for this study is small sample buprenorphine, no buprenorphine cutoff level was 2,000. So it might be a little bit imprecise regarding the calculation. Halfway house patients too can deceive the staff and then, you know, manipulate the intake or even urine test, but I find it very difficult. No quantitative analysis, no consideration for timing of buprenorphine intake, as you mentioned. So, okay. So conclusion about the study is the interpretation of urine testing result can be complicated and thus challenging. The result of this study could help buprenorphine prescribers interpret urine testing result more accurately. This can lead to better clinical decision-making and optimal patient care in office-based buprenorphine treatment. So, going back to the first case, this patient had buprenorphine six, no buprenorphine 26, creatine 68. And the ratio between no buprenorphine and creatine is less than 0.5. Patient complained for cravings and request his increase, his buprenorphine naloxone from 12 to 16. How many people will increase the dosage? How many people decrease the dosage? How many people will maintain the dosage? How many people will sit down and talk with the patient? Okay, all right. So, yeah, that's the whole point. These are the alarming features. We can always increase the dosage, but I would sit down and talk first before changing the dosage. All right, so these are the differences. So far, do you have any question? Yes? This is just a small thing, but why in the study, most of your patients were on eight milligrams of buprenorphine, but most of the urine samples were from patients that take 12 to 16? That's a very good question. So, going back to the, so this goes back to the halfway house resident. They are just coming out of the detox or inpatient. So they usually start with eight milligrams and they're used to eight milligrams. And then, so the patient, and they stay in the resident, in the house for a long time, like up to one year. So at the beginning, they are very motivated and they do the urine test a lot. Let's see. Oops. So there are lots of patient who is on eight milligram. And regarding the urine test, probably one of the reason is that after they move to the residential place, they increase the dosage, usually like 12 or something. So that's, I believe, is the reason that there is lots of urine tests are coming from 12 milligram. But I'm just guessing. That's a good point. Okay. And then regarding the seven hours, this is one small study. Oops. This is one small study. So it's hard to generalize. However, this is just a idea. Time can change the ratio between buprenorphine and no buprenorphine ratio. So, okay. Great questions. All right. So let's move on to the next part three. This time I want you to make a two or three persons group up to four, and then discuss each case. So far, do you have any questions? Okay. Okay. So this is the case of the patient. All right. Please make a two or three group person and discuss if it's appropriate or inappropriate. And the reason why you think it's appropriate or inappropriate. Would you make a two, three person group up to four and then discuss it. Appropriate or inappropriate and why? Okay. So how many people think it's inappropriate? Any of them is inappropriate? Any of, all of them are appropriate? No idea. Okay. All right. So there is the benzo. So, you know, benzo, if it's not prescribed, it's inappropriate. But let's say, let's focus on this part. Buprenorphine, no buprenorphine naloxone. And some people ask, what is the creatinine? So let's talk about that. Okay. So here, it's all like 135, 214, 1092. And then that's the October 18th. Next day, 179, 203, 1039. Is that appropriate? Yeah, I think so. I think so. 182, 193, 1061. Is that appropriate? Yeah, I think so. How about 107, 215, 143? No? Very good. Somebody go a few step ahead. And buprenorphine, no buprenorphine naloxone. The buprenorphine is 1,084. No buprenorphine naloxone is 2,000. You know, this patient started the gabapentin. But if we talk about, look at this. Do you think it's appropriate? No? I don't know if he got extra doses for a reason. Like, if he hospitalized and he's getting loaded up on it, it's like divided doses because of pain management. I don't know. Okay. So the question, okay. So let's look at the question. So here, pretty consistent, right? Yeah. But suddenly there is the big hype. So if this patient is pregnant, I'm wondering if there's some sort of alteration in the metabolism because the patient is pregnant. Hmm. Okay. It would go down, it would go the other way. I'm wondering if they were hospitalized or they're using extra, like they're using illicitly or they're hospitalizing somebody just so they can give an extra dose. I don't know. Okay, so I'll give you a hint. This is the creatinine level. Wow. Wow. So creatinine level, the 40, about 40, about 40, about 100, and more than 350. Yeah. So, you know, that's why this level is very high. All of them are very high because patient is dehydrated. Yeah. Right? So that's why we have to check the creatinine. Okay? Then if, you know, in that case, is this appropriate? Yes. I mean, but if it's good. Well, we could follow the benzos, though. Yeah, benzo is, yeah, benzo, yes. Multiple benzos. Right, right, right. But let's look at the, here. Is it appropriate? Can you just, without asking any question, just give the medication? So I want to know about the kidney transplant. I don't know why. Yeah, yeah, you know, what happened with the kidney here? But, anyone, is there any other issues? Where was the gallopentin in the first, was that added? Yes, gallopentin started, looks like. Oh, it started then. Yeah, around this time. Anyone notice something? Something else? Yes. It's pretty clear, and it seems to be consistent. Oh, it's just something else. It's pretty consistent. You're going, yeah, you are getting close. There's one big drop in the one there. Yes, yes, look at this. Yeah. Okay, so it's pretty consistent, right? About six, five, six, five or so. But what happened here? Missed the dose. Yes, exactly, missed the dose. The patient missed the dose. So that, it was like one day before the urine correction, patient missed the dose. So that's why there is the lower. But patient pretty consistent. So we expect, if they're taking the medication constantly, we expect about five, and this is a good, but patient said that he missed one day. So here, when we look at the urine test, it's really important to have the chronologically check the urine. But also we have to check, we tend to pay attention too much because this is too high. What's going on? And then check creatine. And then when we look at the no buprenorphine creatine ratio usually it's consistent except something. What's going on? So we can ask the patient, what's going on? And then we can, you know, talk. I have a question. On the first three samples, why do you have a level that was higher than the no buprenorphine level and then it drops on the core? This part? This one? Would that be considered normal to have a higher no buprenorphine level? Very good. I'm doing another research on the no buprenorphine level. But I'm glad that, so just a quick preview. So buprenorphine, the half-life of buprenorphine is? 24 to 48 hours. Yes, exactly, one to two days. How about naloxone? What's the half-life of the naloxone? Anyone know? Short. Very short. Very short. You know, even like one to two hours. So if the patient is taking the, is not, missed the dosage the day before, naloxone should be much, much lower because it's going out quickly, as opposed to buprenorphine, which is staying a little bit longer. Oops, sorry. Right? So that's why there is the much greater drop of naloxone because of the difference of the half-life. Does that make sense? Okay, two people, okay. Question? Thank you. Back where I work, we don't use naloxone. It can mean that in the timing of the order, we just don't have it in the unit. So my question is, what is the role of using a type of drug that you recommend adding? Yes, that's a good question. I think the next publication, the article is coming up maybe in one month or two months, talking about naloxone. But naloxone is to confirm the adulteration and to make sure the patient is not taking, if the patient is the monotherapy, just the buprenorphine, and then there is the naloxone, it's strange. So we would check the naloxone for mainly two reasons. Yeah, good question. So, it doesn't matter, I was like, generally naloxone is being extremely quick, right? I'm sorry, could you speak a little bit? As far as my knowledge, naloxone is used to make sure people don't brush it up and inject it, right? Exactly. And so, tending to the bioavailability of naloxone would be like 2% or less. Exactly, very. And it's not just this, like even when we get labs, like in the clinic, I know that naloxone is higher in time, but I really doubt that patients are injecting. I could be wrong. Why does that number show up at all when we're talking about bioavailability? Are there any research that really speaks to that, and I'm not asking people to go into that. That's the exact question I had, so that's why I did the urine test. So what I'm going to do right now, what I'm doing the research is that I took the urine, and those urine coming from someone who is not taking medication, and I dipped the naloxone, I mean, buprenorphine naloxone film, and I also used the water, no urine, and then dipped the buprenorphine naloxone film. We still see the high level of naloxone, which is coming up pretty soon, so please read. But, so the point I want to make is that naloxone, you can see in the urine, does not mean that it's metabolized. It could be just a dissolvent, even to the water. We don't know, but there is the, you know, I mean, the water, and I dipped the film, naloxone is very high. So, you know, so that's a great question, but, okay. Any other questions? In this case, we don't think the person's dipping, right? No. Like, they're just taking it normally. Why do you think so, this patient is not dipping? Yeah, because of the norbuprenorphine that's in there. Yes, it's the, norbuprenorphine is very high. If it's dipping, you know, buprenorphine is very, norbuprenorphine is very high, norbuprenorphine is very low, 50 to one, right? Okay, all right. So, any other questions for this? Can I add to the naloxone question? Are we to assume that everything that's showing up there is within that 2% that's getting absorbed, and then excreted in urine, or is some of it orally swallowed, not getting absorbed at all, and then it's excreted in urine? How are we to assume what's happening with the naloxone from intake to the urine sample? Yes, that's a great question. So, we can't tell, you know, unless we check the naloxone metabolite. So, you know, if it's only checking the naloxone, pre-naloxone, we can't tell. But if we check the naloxone metabolite, we can tell it's metabolized or not. But we need a special lab to check the naloxone glucuronide metabolite. So, somebody hopeful to do that. But, okay, great questions. Okay, all right. So, let me move on to the next one. Okay, all right. So, let's group up with the two, three people, and then discuss this case, if it's appropriate or not. So, this is the case. The, oops, oops, oops, patient is all negative except the buprenorphine 3, 5, 1, and no buprenorphine negative. And naloxone is 89. And then creatinine is 35. By the way, this, all the PowerPoint is available if you go to the app and set that info. So, but, yeah, could you make a two, three group and then discuss if it's appropriate or not? And if it's, why do you think so? You have three minutes. All right, so let's discuss this case. So, buprenorphine 3, 5, 1, no buprenorphine is negative. Naloxone is 89. And the creatinine is 35. And everything else is negative. How many people think that it's appropriate? How many people think it's inappropriate? Okay, so I'd like to hear why people think appropriate or inappropriate. Yes? I don't think it's his urine. So, whose urine did it? Somebody else's urine. Because it's negative for opiate, at the same time, he adulterated by putting the suboxone in the urine. If it was his urine, and he's using opiate, it should come positive. But it's coming negative. At the same time, it doesn't make sense, the ratio between buprenorphine and no buprenorphine. So, most probably, he took somebody else's urine and he dipped that thing in order to come positive. Oh, good. Okay, okay. All right, anyone else? Oh. He just took it. He just took it. Just took it, okay. I don't think it's appropriate, though. Okay. I think it's inappropriate, and he probably just adulterated his urine with buprenorphine. Okay. I think it's possible he just never took it before doing things on the first day because it's gonna be red. Anyone else? Good, good. All right, so let's talk, let's tackle one by one. So, look at the buprenorphine, no buprenorphine ratio. 351, and no buprenorphine is negative. So, it could be adulteration because it's more than 50 to one. There is a problem with that. What's that? Yes. Also, I did the research, putting, dipping the buprenorphine, like just one millimeter, just dipping small amount for three seconds, and still the buprenorphine level is more than the max, usually 1,000. Even small piece, just the dipping, like three seconds, it's get much higher than this. Oops, oops. Much higher than this number, and so does naloxone. Also, yeah, so, and then the creatine level is good, right? Maybe they might dilute it to half and half, so it could be, it was like a 70, or even like, you know, more than that, and then it could be diluted. That's possible. In that case, adulteration is possible, but naloxone is low, which is unlikely because when we did the buprenorphine-naloxone film, buprenorphine and naloxone, both of them are usually more than measurable, more than usually 1,000. So, and then what was the other, what was the other? Just took it. There's one- First time. First time. There's one problem with that. What's that? Metabolize something. Huh? There's no more- There's no metabolite, yeah. Two nanograms is very little, it should show something, yeah. So, they just took it. So, before it's metabolized to buprenorphine to no buprenorphine. Then, why the naloxone is so low? The peak of naloxone is very, very quick. So, usually when they take it, naloxone is higher than buprenorphine. So, why is that? Any other comments? You know, I had a hard time, and then, think, and then, oops, sorry. This is what we come up with. Is this an adulterated sample? And if so, but the buprenorphine naloxone levels are low for adulteration. Okay, and then if, did this patient took buprenorphine naloxone immediately before the urine correction? But naloxone is usually higher than buprenorphine because naloxone is shorter peak in half-life than buprenorphine. So, the enzyme that metabolize naloxone are inhibited genetically with a medical issue or by medication. Then, we can explain one or two. But the naloxone, there is something going on with the naloxone level. So, there might be a variation. Yes? But it starts with no naloxone. Oh. Oh. Then, why any naloxone? Yes, but yes, then why there, I hear that. Then, why there is the naloxone? From the debut film. Oh. I thought there would be more buprenorphine. If even small piece, small part of the film is dipped, it's very, very high. The buprenorphine level is very high, usually more than 1,000. So, they dip really small amount and dilute it, that's possible. Yeah, but those are good thinking. So, it's very interesting to look at that. If I, I would look at the chronological urine test of this patient and see if it's the pattern. What if he did, what if he used a strip? Strip? Like a strip that he had used previously and they, you know, scraped off or whatever, so there's barely any on him. Oh, very small amount. But then, you know, then the naloxone should be higher, though, even though the attrition like that. There's another way people do it, is they'll use, if they're taking tablets, they just rub their fingers on the tablets and put their fingers in the urine. So, there is the possibility that patient took the, and I don't know how much, I don't know if there's, you know, is there more buprenorphine that comes off on their fingers than naloxone or, you know. Those are the good thoughts, good thoughts. So, what we have to do is we have to check the chronological urine test. We have to check, you know, like weekly and see if his pattern continues or this is just a variation. And then, we can look at the answer. But I thought this is a very interesting case. I was thinking and thinking and I can't think of, but one of the reasons that I can come up with is that maybe naloxone enzyme might be inhibited somehow or it could be no variation, depends on the genetic or medication. So, in our clinic, we have cameras, but on top of that, if we were to see something like this, we would do a certain stop stream at the same time to ensure that that was observed. Yes, yes, yes. You know, so the camera or observed, you know, there is so many ways to monitor. Yes, good, good. All right. I guess that's the whole presentation. Do you have any questions or? Yes. Oh, if you can come to the mic, that'd be great. Yeah, this is about creatinine a little bit more in terms of dilution and stuff, not directly related to buprenorphine, but I'm always troubled or confused about creatinine because I follow one person who takes clonazepam consistently, and whenever her creatinine is, you know, under 25, clonazepam doesn't show up in the urine. If it's over 25, clonazepam does show up. So it's not dilute, per se, but there is definitely a cutoff point and she gets a lot of urine. So that's kind of interesting in terms of that. I have another patient who always has creatinine under 20, not always, but a lot, and as low as 15 and 16, but the specific gravity is always normal. And so I was just wondering, like, how well we can use creatinine in either of those situations or what we can learn about creatinine. Very good. I have a similar situation. So this is, one thing we can look at is that if they're manipulating, their creatinine level is up and down. But if it's medical issues, their creatinine level is usually consistent, 15, 16, 17, or something like that. So I have a patient who is always like a 15, 16 constantly. And when I look at her, she's always holding the water bottle and then she's drinking constantly because she believed that drinking lots of water is good for the health. So one thing to differentiate manipulation versus a certain behavior or a medical issue is the consistency or variation. If it's 15 and constantly 15 and other things are good, then probably it's not manipulation, it's more like some other issues, I believe. Yeah, I have a question for you. I just want to ask you practically. I mean, I see a lot of stuff on some of the patients but at the same time, I'm not the police and I don't want to be like do FBI investigation every time they use me, like kind of. So I want to ask you like practically, how often would you do these? Because they come with a cost for money and also like as it seems, sometimes it's obvious but sometimes it's very confusing to go like the last case that would be, so it would make me like, you know, more complicated for the patient. So how often do you use them or clinically when would be the time you would do this level creatinine and naloxone and move and ask the lab to do that? So some, I believe, recommend at least eight times a year of the urine test but if it's for unstable patient, more frequently, like you know, weekly or something. So it really depends on the patient but if the money, the finances is the issue, I will talk with the patient. So you brought a good point. If we see this kind of issues, like you know, manipulation, adulteration, how you talk with the patient? What I usually do is that I would just present the case, you know, because we are on the Zoom so we can share the urine test and say, look, you know, my supervisor asked me a question. This is a little bit similar to adulteration or dilution urine test result and I trust you so I don't think it's, you know, it's not the case but I wanted to talk with you and I'll just be quiet and let them talk, you know, nothing judgmental, just, you know, presenting the case and then they will say something and then, but they will notice, they know that we are paying attention and usually next time, their urine is good. So which, you know, we have to wait for that, you know, to visit because, you know, we have to check the next time and so, but, you know, the way to present the case and discuss the case is very sensitive and then so we just present the result neutrally without judgment and then let them talk. But, yeah, did that answer my question? No, no, yeah, your answer but I was like, just like kind of wondering practically, I mean, you said you do it eight times a year, like these tests eight times a year because it would be like, I'm just aware I work, like for example, where I work, we do like, if someone is stable, we do a regular urine test every 90 days, I mean, there's no way I can do all these levels every week, like, so I'm just wondering, like, how often you are doing that? Yeah, that's, yeah, especially, you know, telemedicine started, it's kind of getting harder to do the urine test, yeah, so we have to, you know, it takes a little bit longer to monitor, yeah. Okay, good questions, any other questions? All right, I'll be around, so if you have any question, please, you know, feel free. If you have any cases that you don't understand, you know, you want to consult, feel free to send this to this email address, and then on weekends, I'm going to respond to your email, so if you're in any consultation. All right, thank you so much for coming.

Dr. Hiroko Furo

addiction medicine

University of Texas at San Antonio

urine test results

manipulation in buprenorphine treatment

research findings

case scenarios

interpreting urine test results

clinical decisions

office-based buprenorphine treatment

question and answer session